Methods of treatment for opioid-induced ventilatory depression and muscle rigidity

Abstract

Disclosed herein are methods for treating opioid induced conditions, particularly methods are disclosed for treating opioid-induced respiratory depression and muscle rigidity (e.g., chest wall rigidity), for example as a result of opioid exposure or administration.

Description

METHODS OF TREATMENT FOR OPIOID-INDUCED VENTILATORY DEPRESSIONAND MUSCLE RIGIDITYTECHNICAL FIELD

[0001] Disclosed herein are methods for treating opioid induced conditions, particularly methods are disclosed for treating opioid-induced respiratory depression and muscle rigidity (e.g., chest wall rigidity), without risk of withdrawal and / or without reducing the level of analgesia, as a result of opioid exposure or administration.CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application Nos. 63 / 655,326, filed June 3, 2024, and 63 / 761,602, filed February 21, 2025, the contents of which are herein incorporated by reference in their entirety.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0003] This invention was made with government support under DA053551 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND

[0004] Among the approximate 100,000 annually identified unintentional overdose deaths in the United States (involving any drugs or medications), about 70% are currently related to the use of opioids, in large part due to the increased prevalence of fentanyl usage. The current treatment of an opioid overdose is a rapid intravenous or intranasal administration of the opioid antagonist naloxone, along with cardio-pulmonary resuscitation maneuvers when victims are found in cardio-respiratory arrest. The doses of naloxone are associated with a reversal of sedative effects, which can produce harmful acute withdrawal symptoms. These withdrawal symptoms are even more of a concern in poly substance abusers who take opioid with other drugs with potent excitatory effects, such as amphetamine or cocaine, and who can become very agitated and extremely combative after naloxone. Thus, methods that allow for a correction of opioid-induced respiratory depression without reversing the sedative effects of the opioid are needed.SUMMARY

[0005] In one aspect, disclosed herein are methods of for treating opioid-induced respiratory depression and / or muscle rigidity in a subject need thereof. In some embodiments, the methods comprise administering to the subject a therapeutically effective dose of nalfurafine. In some embodiments, the subject exhibits respiratory depression. In some embodiments, the muscle rigidity is chest wall muscle rigidity, also known as wooden chest syndrome (WCS).

[0006] In some embodiments, the subject received an overdose of an opioid. In some embodiments, the subject received oral or topical exposure to or administration of the opioid. In some embodiments, the subject received a dose of the opioid intravenously. In some embodiments, the dose (e.g., the intravenous dose) was administered at greater than 30 pg / min.

[0007] In some embodiments, the opioid is fentanyl or an analog thereof.

[0008] In some embodiments, the subject received a dose, overdose, or exposure to one or more opioids. In some embodiments, the one or more opioids comprise fentanyl or an analog thereof.

[0009] In some embodiments, the therapeutically effective dose of nalfurafine is administered intravenously, intramuscularly, subcutaneously, or intranasally.

[0010] In some embodiments, the therapeutically effective dose of nalfurafine is 0.01 mg / kg to 0.1 mg / kg administered intravenously. In some embodiments, the method does not decrease sedation or analgesia level of the subject.

[0011] In another aspect, disclosed herein are kits comprising one or more therapeutically effective doses of nalfurafine and a delivery device or system.

[0012] Other aspects and embodiments of the disclosure will be apparent in light of the following detailed description and accompanying figures.BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1 shows the effects of nalfurafine on fentanyl-induced muscle rigidity in nonsedated rats (n=8). Normal score is zero (no rigidity, score of 6 maximal contracture of the forelimb, hindlimb and hack muscles), Fentanyl increases rigidity to a maximal level, an effect reversed by nalfurafine. Data are shown as Mean ± SD.

[0014] FIGS. 2A-2F show the effects of nalfurafine on fentanyl-induced ventilatory depression in non-sedated rats. Changes over time in frequency (FIGS. 2A and 2C), minuteventilation (VE, FIGS. 2C and 2D), and tidal volume (VT, FIGS. 2E and 2F). Breathing frequency and minute ventilation are shown as mean ± SD. Note that in contrast to nalfurafine at 1 mg / kg (FIGS. 2A and 2C), low dose nalfurafine 0.1 mg / kg as well as the kappa agonist U50488 (Img / kg) (FIGS. 2B and 2D) have no antidotal effects on breathing when compared to saline.

[0015] FIGS. 3A-3F show nalfurafine reverses fentanyl-induced muscle rigidity without affecting sedation or nociceptive response in non-sedated rats. Changes in muscle rigidity (FIGS. 3A and 3B), reflex response (FIGS. 3C and 3D), and toe pinch (FIGS. 3E and 3F) elicited by a 15-sec bolus injection of fentanyl (150 ug / kg) and subsequent injection of saline, nalfurafine (1 mg / kg) or U50488 (1 mg / kg) in rats without prior sedation are shown. Rigidity was scored at the forelimb, hindlimb, and back / tail using a three-point scale: 2 = intense tonic muscle contractions observed immediately after fentanyl; 1 = noticeably decreased, yet persistent, tonic muscle contraction; and 0 = complete resolution of rigidity. Sedation was evaluated by reflex response: grasping, righting reflex, corneal reflex (air puff), and auditory reflex (clap response). Response to painful stimuli was determined using a forelimb toe pinch. 0 = no response, and 2 = full reflex response. * P < 0.05, a significant change from saline values within the time point, f P < 0.05, U50488 versus nalfurafine at the same time point in FIGS. 3A, 3C, and 3E. N = 6 for each group, data are shown as mean ± SD.

[0016] FIG. 4 shows examples of the effects of bolus injections of fentanyl, followed by either saline, nalfurafine, or U50488 on instantaneous respiratory flow (v) in non-anesthetized rats. A bolus fentanyl injection (150 ug / kg) caused a rapid apnea punctuated with expiratory contractions. In rats treated with saline (top), rhythmic breathing activity resumed. Rats that received 1 mg / kg nalfurafine (middle) had a large increase in v, which plateaued and was maintained above that of saline for the remaining 25 min. Rats treated with 1 mg / kg U50488 (bottom) also resumed rhythmic breathing activity, but not to the level of nalfurafine.

[0017] FIGS. 5A-5C show statistical comparisons of the effects of bolus injections of fentanyl, followed by either saline, nalfurafine, or U50488, on respiration in non-anesthetized rats. Changes in minute ventilation (VE, FIG. 5A), frequency (FIG. 5B), and tidal volume (VT, FIG. 5C) in non-sedated, freely moving rats after injection of 150 ug / kg fentanyl followed by either saline (n = 12), 1 mg / kg (n = 12) or 0.1 mg / kg (n = 8) nalfurafine, or 1 mg / kg U50488 (n = 11). The baseline (BL) was averaged over 15 minutes before fentanyl administration. Peak (Pk)responses were taken 90 sec after treatment with saline, nalfurafine, or U50488. Subsequent bins are 5-10, 10-20, and 20-30 min averages. The data are shown as mean ± SD. * P < 0.05, a significant change from baseline (BL) values within the group, f P < 0.05, treatment versus saline at the corresponding time point.

[0018] FIGS. 6A and 6B show changes in VE / VO2 and VE / VCO2 elicited by bolus injections of fentanyl, followed by either saline, nalfurafine, or U50488 in non-sedated rats. Changes in ventilatory equivalent for oxygen (VE / VO2, FIG. 6A), and ventilatory efficiency (VE / VCO2, FIG. 6B) in non-sedated, freely moving rats after injection of 150 ug / kg fentanyl followed by either: saline (n = 12), 1 mg / kg (n = 12) or 0.1 mg / kg (n = 8) nalfurafine, or 1 mg / kg U50488 (n = 11). The baseline (BL) was averaged over 15 minutes. Responses were taken after treatment with saline, nalfurafine, or U50488. bins are 5-10, 10-20, and 20-30 min averages. The data are shown as mean ± SD. *P < 0.05, a significant change from baseline (BL) values within the group. fP < 0.05, treatment versus saline at the corresponding time point.

[0019] FIGS. 7A-7D show bolus injections of nalfurafine or U50488 alone do not stimulate respiration in non-anesthetized rats. Representative examples of the effects of bolus injections of 1 mg / kg nalfurafine (FIG. 7A, n = 6) or 1 mg / kg U50488 (FIG. 7B, n = 5) on instantaneous respiratory flow (v). Changes in minute ventilation (FIG. 7C) are shown as mean ± SEM.Changes in minute ventilation (VE, FIG. 7D) did not show statistical differences between the groups.DETAILED DESCRIPTION

[0020] As disclosed herein, the kappa opioid receptor agonist nalfurafine acts on the structures responsible for severe muscle rigidity and upper airway obstruction as well as on respiratory neurons to restore breathing without affecting sedation or analgesia. There is no evidence supporting a direct stimulatory effect on ventilation by kappa agonists. The stimulatory effects of nalfurafine on ventilation are very rapid and cannot be reproduced by the kappa agonist U50488, even at concentrations up to 10 mg / kg.

[0021] Section headings as used in this section and the entire disclosure herein are merely for organizational purposes and are not intended to be limiting.Definitions

[0022] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of,” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not. The use of the term “at least one” followed by a list of one or more items (for example, “at least one of A and B”) is to be construed to mean one item selected from the listed items (A or B) or any combination of two or more of the listed items (A and B), unless otherwise indicated herein or clearly contradicted by context.

[0023] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

[0024] As used herein, the modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to ±10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9 - 1.1. Other meanings of “about” may be apparent from the context, such as rounding off; for example, “about 1” may also mean from 0.5 to 1.4.

[0025] Unless otherwise defined herein, scientific, and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear; in the event, however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0026] An “effective amount” refers to an amount sufficient to elicit a desired biological response (e.g., treating a condition). As will be appreciated by those skilled in the art, the effective amount may vary depending on such factors as the desired biological endpoint, the pharmacokinetics, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment. For example, a “therapeutically effective amount” is an amount sufficient to provide a therapeutic benefit in the treatment of a condition, or to delay or minimize one or more symptoms associated with the condition. In some embodiments, a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition. A therapeutically effective amount means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0027] The term “improve,” “increase,” or “reduce,” as used herein, indicates values that are relative to a control. In some embodiments, a suitable control is a baseline measurement, such as a measurement in the same individual prior to administration or onset of symptoms or a measurement in a matched control individual. For example, a “control individual” is an individual who is approximately the same age and / or gender as the individual being treated.

[0028] A “subject” or “patient” may be human or non-human and may include, for example, animal strains or species used as “model systems” for research purposes, such a mouse model as described herein. Likewise, subject may include either adults or juveniles (e.g., children). Moreover, subject may mean any living organism, preferably a mammal (e.g., humans and nonhumans) that may benefit from the administration of compositions contemplated herein. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, and the like. In one embodiment, the mammal is a human.

[0029] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or condition, or one or more signs or symptoms thereof. In some embodiments, “treatment,” “treat,” and “treating” require that signs or symptoms of the disease disorder or condition have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0030] As used herein, the terms “providing,” “administering,” and “introducing,” are used interchangeably herein and refer to the placement into a cell, organism, or subject by a method or route which results in at least partial localization to a desired site. The administration can be by any appropriate route which results in delivery to a desired location in the cell, organism, or subject.

[0031] Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.Methods for Treating Opioid-Induced Conditions

[0032] Provided herein are methods for treating opioid-induced respiratory depression and / or muscle rigidity. In some embodiments, the methods comprise administering to the subject in need thereof a therapeutically effective dose of nalfurafine, or a pharmaceutically acceptable salt thereof.

[0033] The muscle rigidity may include chest wall rigidity. Opioid-induced chest wall rigidity is characterized by an increase in muscle tone in the thoracic and abdominal muscles after exposure to an opioid, e.g., fentanyl. Chest wall rigidity, also known as wooden chest syndrome, can cause respiratory distress, e.g., respiratory depression. Chest wall rigidity can manifest as episodic breath-holding spells, tensing of abdominal muscles, firmly locked jaw, stiff extremities, and decorticate posturing with arms bent in towards the body, legs held out straight, clenched fists, and overall stiffness. Chest wall rigidity may be accompanied by hypoxia andhypertension. Treating chest wall rigidity can result in a decrease in the episodes or a decrease in tensing of abdominal muscles, locked jaw, stiff extremities, and decorticate posturing to any degree or to fully normal states.

[0034] Respiratory depression is a common problem with opioid use. It is not always possible to predict the timing or severity of respiratory depression due to the number of contributing factors including age, sex, body-mass index, presence of co-morbidities, and concomitant medications administered. Some risk factors are very strong predictors of respiratory complications, e.g., when the opioid is used in a clinical post-operative setting. For example, in bariatric patients the incidence of deleterious respiratory events post-operatively may be as high as 100%.

[0035] Respiratory volume monitoring (RVM) measurements can be used to monitor and measure respiratory depression in a subject. Respiratory depression is a decrease in respiratory volumes, minute ventilation curve characteristics, or variability. Respiratory depression may result from a decrease of greater than 2%, 5%, 10%, 20%, 30%, 40%, 50% or more of any of the RVM measurements. Treatment of respiratory depression results in any increase in any of the RVM measurements from the depressed level up to baseline levels, e.g., levels seen in normal individuals or level prior to opioid exposure or administration.

[0036] Following treatment, a rapid and prolonged increase in breathing occurs in the subject. In some embodiments the methods increase breathing, thereby treating respiratory depression, in less than 5 min. An increase in breathing may be seen in less than 5, 4, 3, 2, or 1 minute following conducting the methods as described herein (e.g., administration of nalfurafine). The increase in breathing, as compared to the levels during the opioid-induced respiratory depression, may be maintained for greater than 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or more or more minutes following conducting the methods as described herein (e g., administration of nalfurafine).

[0037] The terms “opioid” as used herein is to be taken to mean at least one of a natural or synthetic or semi-synthetic narcotics. Exemplary opioids include codeine, phenazocine, tilidine, tramadol, meperidine, sufentanil, prodine, methadone, pentazocine, oxycodone, oxymorphone, hydrocodone, hydromorphone, tapentadol, morphine, buprenorphine, heroin, opium, fentanyl, and derivatives and analogs thereof. For example, analogs of fentanyl include, but are not limited to: fentanyl, 2,5-dimethylfentanyl, 3 -allylfentanyl, 3 -methyl butyrfentanyl, 3 -methylfentanyl, 3-methylthiofentanyl, 4-fluorobutyrfentanyl, p-chloroisobutyrfentanyl, p-fluoroisobutyrfentanyl, 4- fluorofentanyl, 4-phenylfentanyl, 4-methoxybutyrfentanyl, acrylfentanyl, a- methylacetylfentanyl, a-methylbutyrfentanyl, a-methylfentanyl, a-methylthiofentanyl, acetylfentanyl, alfentanyl, benzylfentanyl, P-hydroxyfentanyl, P-hydroxythiofentanyl, methylfentanyl, butyrfentanyl, brifentanyl, carfentanyl, cyclopentylfentanyl, isobutyrfentanyl, furanylfentanyl, furanylethylfentanyl, lofentanyl, N-methylcarfentanyl, methoxyacetylfentanyl, mirfentanyl, ocfentanyl, ohm efentanyl, R-30490, remifentanil, sufentanyl, thenylfentanyl, thiofentanyl, trefentanyl, and valerylfentanyl.

[0038] The subject may be exposed to or administered the one or more opioids in a variety of ways, including but not limited to orally (e.g., by ingestion); topically (including e.g. transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through mouth or nose); and parenterally (e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal injection). If the subject is exposed to or administered more than one opioid, each opioid can be exposed or administered to the subject by the same or different means. In some embodiments, the subject was orally or topically exposed to or administered the one or more opioids. In some embodiments, the subject received a dose of the opioid intravenously.

[0039] In some embodiments, the subject received an overdose of one or more opioids. In some embodiments, the subject received an overdose of fentanyl alone or in combination with one or more additional opioids. As used herein the overdose describe the ingestion or application of one or more opioids, individually or combined, in quantities greater than are recommended, prescribed, or generally practiced. An overdose may be intentional or accidental. The opioid overdose may induce respiratory depression and / or muscle rigidity in the subject at any time following overdose.

[0040] In some embodiments, the subject received a dose of one or more opioids in quantities used in general practice but with rapid administration, e.g., over a short period of time. The dose may be generally considered safe, but the subject may exhibit respiratory depression and / or muscle rigidity as a result of the rapid administration. In select embodiments, the subjectreceived a dose of fentanyl with rapid administration. For example, rapid administration of fentanyl may be greater than 5, 10, 30, 50, or 100 ug / min.

[0041] The methods comprise administering to a subject a therapeutically effective dose of nalfurafine, or a pharmaceutically acceptable salt thereof.

[0042] Nalfurafine, (2E)- -[(5a,6P)-17-(Cyclopropylmethyl)-3,14-dihydroxy-4,5- epoxymorphinan-6-yl]-3-(3-furyl)-A-methylacrylamide, is an atypical K-opioid receptor agonist. It does not produce hallucinogenic (psychotomimetic) effects or cause the typical dysphoric adverse effects in humans unlike other K-opioid receptor agonists. As a 4,5- epoxymorphinan derivative nalfurafine is structurally different from other K-opioid receptor agonists.

[0043] The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bi sulfate, butyrate, camphorate, camphorsulfonate, di gluconate, glycerophosphate, hemi sulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, tri chloroacetate, trifluoroacetate, glutamate, paratoluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like. For example, nalfurafine may be provided as nalfurafine hydrochloride.

[0044] In the methods disclosed herein, administration of nalfurafine may be by any convenient route of administration, whether systemically / peripherally, including but not limited to, oral (e.g., by ingestion); topical (including e.g. transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., an aerosol, e.g., through mouth or nose); and parenteral (e.g., by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid,and intrasternal injection). In select embodiments, the nalfurafine is administered intravenously, intramuscularly, subcutaneously, or intranasally.

[0045] Nalfurafine may be administered with a pharmaceutically acceptable carrier or excipient as a pharmaceutical composition, which are also within the scope of the present disclosure.

[0046] The phrase “pharmaceutically acceptable,” as used in connection with compositions and / or cells of the present disclosure, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and do not typically produce untoward reactions when administered to a subject (e.g., a mammal, a human). Preferably, as used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans. “Acceptable” means that the carrier is compatible with the active ingredient of the composition (e.g., the nucleic acids, vectors, cells, or therapeutic antibodies) and does not negatively affect the subject to which the composition(s) are administered. Any of the pharmaceutical compositions and / or cells to be used in the present methods can comprise pharmaceutically acceptable carriers, excipients, or stabilizers in the form of lyophilized formations or aqueous solutions.

[0047] Pharmaceutically acceptable carriers, including buffers, are well known in the art, and may comprise phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives; low molecular weight polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; amino acids; hydrophobic polymers; monosaccharides; disaccharides; and other carbohydrates; metal complexes; and / or non-ionic surfactants. See, e.g., Remington: The Science and Practice of Pharmacy 20th Ed. (2000) Lippincott Williams and Wilkins, Ed. K. E. Hoover.

[0048] In general, however, an effective and suitable dose of nalfurafine will often be in the range of from about 0.001 mg / kg to about 10 mg / kg. For example, an effective dose may be in the range from about 0.01 mg / kg to about 7.5 mg / kg, such as about 0.01 mg / kg to about 0.05 mg / kg, about 0.01 mg / kg to about 0.10 mg / kg, about 0.01 mg / kg to about 0.50 mg / kg, about 0.01 mg / kg to about 1.0 mg / kg, about 0.01 mg / kg to about 2.0 mg / kg, about 0.01 mg / kg to about 3.0 mg / kg, about 0.01 mg / kg to about 4.0 mg / kg, about 0.01 mg / kg to about 5.0 mg / kg, about 0.01mg / kg to about 6.0 mg / kg, or about 0.01 mg / kg to about 7.0 mg / kg. In select embodiments, the effective dose of nalfurafine is 0.01 mg to 0.1 mg / kg.

[0049] Administration in vivo can be in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub- doses per day. For example, the nalfurafine may be administered once, on a continuous basis (e.g. by an intravenous drip), or on a periodic / intermittent basis, for example about once per hour, about once per two hours, about once per four hours, about once per eight hours, about once per twelve hours, and about once per day. The sub-dose itself may be further divided, e.g., into a number of discrete, loosely spaced administrations.

[0050] When utilized as a method of treatment, the effective amount and / or dosage of the nalfurafine may depend on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size, gender and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. In some embodiments, the subject is a human.

[0051] Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.

[0052] Other therapies may be used in combination with the nalfurafine. “In combination,” as used herein, means that two (or more) different treatments are delivered to the subject during the course of the treatment. The additional therapy may be administered at the same time as the nalfurafine, as simultaneous or concurrent delivery. For example, either in the same composition or in a separate composition administered at substantially the same time as the nalfurafine. In some embodiments, the additional therapy may precede or follow the nalfurafine administration. The additional therapy may include administration of an additional therapeutic agent, or a therapy not connected to administration of another agent including providing mechanical ventilation.Kits

[0053] In another aspect, the disclosure provides kits or systems comprising one or more doses of nalfurafine and, optionally, one or more containers or devices for use with the methods disclosed herein, for example delivery devices and systems. In some embodiments, the kit comprises a single-use or single dose of nalfurafine and a delivery device or system.

[0054] Delivery devices and systems include, but are not limited to: a pre-filled syringe, a vial and syringe, an injection pen, an auto-injector, a dripper and iv bag, a pump, a dermal patch, an eye / ear / nose dropper, a dropper bottle, a nasal pump sprayer or spray system for liquid or powders, mucosal atomization device, nebulizers, nasal douches, and the like.

[0055] The kits or systems can also comprise other agents and / or products co-packaged or co-formulated with the other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising another agent for delivery to a subject. Individual member components of the kits may be physically packaged together or separately.

[0056] It is understood that the disclosed kits can be employed in connection with the disclosed methods. The kits can also comprise instructions for using the components of the kit. The instructions are relevant materials or methodologies pertaining to the kit. The materials may include any combination of the following: background information, list of components, brief or detailed protocols for using the compositions, troubleshooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0057] The kits provided herein are in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging, and the like. Individual member components of the kits may be physically packaged together or separately.

[0058] The following examples further illustrate aspects of the disclosure, but should not be construed as in any way limiting its scope.EXAMPLESMaterials and Methods

[0059] Experiments were performed in non-sedated rats. On the day of the study, rats were briefly sedated (3.5% isoflurane) for about 15 minutes to place a heparinized, double lumen,venous catheter in the dorsal vein of the tail. Two to three hours are given for full recovery before doing the study. Methodology has been described in previous publications. A custom- designed, leak-proof, acrylic cylinder (internal volume 1.4 liters) was used for determination of ventilation and pulmonary gas exchange. Air was delivered through the inlet port of the plethysmographic chamber using a precision rotameter (flow of ~2.5 L / min). The fractions of CO2 and O2 are determined in the gas leaving the chamber for computation of V02 and VCO2. The analog output signals are fed into a digital data acquisition system (400 Hz, PowerLab / LabChart; AD Instruments, Colorado Springs CO), displayed online and stored for additional analysis.

[0060] Fentanyl was administered IV at the dose of 150 microg / kg over 10 seconds; a dose previously shown to induce a rapid apnea, followed by a depressed breathing pattern for several hours that can be spontaneously lethal, while producing muscle stiffness in all animals. Minute ventilation, breathing frequency and tidal volume were continuously determined over a three- hour period. Saline, nalfurafine, or U50-488 were infused 5 minutes after the end of fentanyl infusion.

[0061] Each surviving animal was assessed for neuro-function, rigidity score and behavior every minute for 30 minutes, then every hour during the first 6 hours, and again at 12 and 24 hours, as previously described.

[0062] Studies consisted of two distinct approaches in separate groups of animals: i) muscle rigidity / sedation scoring and ii) ventilatory measurements. For the muscle rigidity / sedation scoring studies, a group of 18 male and female rats weighing 325 ± 33 g was used. Each animal was used once. In a separate group of 25 adult male and female rats weighing 337 ± 22 g, ventilation and pulmonary gas exchange were measured using an open-flow plethysmograph. To reduce the number of animals used for this study, some rats were used more than once and no more than three times. Fifty-eight plethysmography experiments were performed: 25 rats were studied once, 23 were studied twice, and 10 were studied 3 times. No rats were used for the same drug treatment twice, all conditions had at least two rats being studied for the first time, and no group had more than two rats being studied for a third time in the seven total groups. Animals were given at least a week between experiments. It has been shown that tolerance does not develop for fentanyl-induced unconsciousness, muscle rigidity, or respiratory depression whengiven twice a week. Rats were monitored daily after each experiment to ensure within 2-3 days that they had gained weight and demonstrated normal behavior.

[0063] Drugs and Dose Justification Drugs used in the study included Fentanyl (Fentanyl Citrate Injection [50 g / ml], Hospira, Inc., USA), Nalfurafine hydrochloride (A12579, AdooQ Bioscience, Irvine, CA), (-)-U-50488 hydrochloride (0496, Tocris, Bristol UK), naloxone (Naloxone Hydrochloride Injection, [0.4 mg / ml], Somerset Therapeutics, LLC, USA). Dilutions, when needed, were always made with sterile saline.

[0064] The effects of fentanyl overdose 50 to 300 pg / kg IV were previously investigated in rats and found that at the dose of 150 pg / kg, rigidity was present in every animal with low mortality. Therefore, 150 pg / kg was the fentanyl dose used in this study, administered IV over 15 seconds. Doses of nalfurafine and U50488 were chosen based on literature sources and initial ventilatory studies. For nalfurafine, based in a review presented by the European Medicine Agency, ventilatory studies were started using 0.1 and 1 mg / kg, doses with reported selective KOR agonist properties but below toxicity. For U50488, based on published in vivo studies of IV administration in rats, the studies were started with 1 mg / kg and the dose was increased based on the results.

[0065] Muscle Rigidity and Sedation Scoring A clinical scoring method was utilized to assess the effects of nalfurafine versus saline on fentanyl-induced muscle rigidity, sedation, and response to painful stimuli. Rats received 150 pg / kg fentanyl IV and were then monitored for 30 minutes. Five minutes after fentanyl administration, rats were given a bolus of either saline (volume control, 2 ml / kg), 1 mg / kg nalfurafine, or 1 mg / kg U50488. Scoring was performed every minute during the first 10 minutes and every other minute thereafter until 30 minutes postfentanyl injection.

[0066] Rigidity was scored at the forelimbs, hindlimbs, and back / tail using a three-point scale: a score of 2 represented intense tonic muscle contractions observed immediately after fentanyl (maximal fentanyl-induced muscle rigidity (FIMR)); a score of 1 indicated a noticeably decreased, yet persistent, tonic muscle contraction; and a score of 0 reflected complete resolution of rigidity. Scores were assigned in a blinded manner relative to the treatment administered after the fentanyl (saline, nalfurafine or U50488), referencing the initial maximal FIMR for consistency. This scoring method was chosen after attempts to directly measure muscle tension (in the triceps surae), and intramuscular pressure proved impractical due to the need for priorsedation, which interfered with the model. This blinded clinical scoring provided a practical and sensitive alternative for evaluating (FIMR). Data from the three sites (forelimb, hindlimb, back / tail) were analyzed by averaging the mean of individual animal scores in 5 min bins and taking the mean of those scores of animals within the same treatment group, and then compared over time and between conditions.

[0067] Sedation was evaluated by the presence or absence of a reflex response: grasping, righting reflex, corneal reflex (air puff), and auditory reflex (clap response). Response to painful stimuli was determined using a forelimb toe pinch. A score of 0 indicated no reflex response, and 2 indicated a full reflex response for both conditions.

[0068] Whole-Body Plethysmography On the day of the study, unrestrained rats were placed inside a custom-designed, leak-proof acrylic plethysmographic chamber (1.4 L volume) to measure ventilation and pulmonary gas exchange {Haouzi, 2020 #63;Bell, 2009 #45}. Airflow was delivered via a precision rotameter to the chamber's inlet port (flow of ~ 1.5 L / min) from a tank of compressed medical-grade air (Linde Gas, Danbury CT). Both inlet and outlet ports were connected to independent bi-directional screen pneumotachs (series 8421, Hans Rudolph, Shawnee, KS) via non-compliant tubing and linked to a pressure transducer (Pneumotach amplifier 1, series 1110, Hans Rudolph) to measure airflow. Each pneumotachograph was independently calibrated by passing a fixed volume of air via a syringe and integrating the flow signal to establish flow over time before each experiment. With the sensors in circuit with the empty chamber, the rotameter was adjusted to the desired flow using the two flow signals to ensure there were no leaks and to account for the small resistance of the system. Semi- quantitative measurements of minute ventilation (VE), frequency (f), and sum tidal volume (VT) were calculated using the outlet flow signal. Gas was sampled from the chamber outlet flow and analyzed using a Gemini Respiratory Analyzer (CWE, Inc.) to measure %CO2 and %C>2. These were used to compute oxygen consumption (VO2) and carbon dioxide production (VCO2) using the inlet flow and known gas composition (21% O2, 0% CO2) from the tank with the following equations:VCO2 (ml / min) = Inflow (ml / s) * %CCh measured (from outflow) * (60 / 100) VO2 (ml / min) = Inflow (ml / s) * 21- %C>2 measured (from outflow) * (60 / 100) Analog signals were recorded using a digital data acquisition system (PowerLab / LabChart; AD Instruments, Colorado Springs, CO) at a sampling rate of 400 Hz for further analysis.

[0069] Rats were acclimated in the plethysmograph chamber for at least 30 minutes to establish baseline breathing recordings. They were then briefly removed to connect the venous catheter to an extension line using leak-proof adapters, allowing the infusion line to be externally connected to a syringe. After flushing the catheter with saline, rats were returned to the chamber and allowed an additional 5 minutes to ensure proper equipment and catheter functionality.

[0070] Experimental Protocols For all rats that received fentanyl, a bolus IV injection of 150 pg / kg (50 pg / mL solution) was administered over 15 seconds and flushed with 1 ml of sterile saline. This dose and administration time were previously established to induce rapid apnea with a gradual recovery in most rats. Five minutes from the start of the fentanyl bolus, the second treatment was administered IV, either: saline (volume control, 2 ml / kg), nalfurafine 1 mg / kg (0.5 mg / ml), nalfurafine 0.1 mg / kg (0.05 mg / ml), U50488 1 mg / kg (0.5 mg / ml), U50488 10 mg / kg (5 mg / ml). All were given over 15 seconds and flushed with an additional 1 ml of saline over 15 seconds. A total volume injected over this time course was, therefore, 3.011 ml for a 337 g rat (average weight of group). In separate groups, some rats received either nalfurafine (1 mg / kg, 0.5 mg / ml) or U50488 (1 mg / kg, 0.5 mg / ml) alone. All animals were monitored for 30 minutes following the initial fentanyl injection.

[0071] Data Analysis, Representation, and Statistics Rigidity and sedation scores are shown as mean ± SD and compared using Friedman test with multiple comparisons for the time course data. A Kruskal -Wallis test with multiple comparisons was applied to the averaged column data. For plethysmography studies, a band-pass filter was applied to the flow signal. A low cut-off frequency of > 0.1 Hz was used to remove the DC component, and a high cut-off frequency of < 5 Hz was used to subtract ambient signal noise and heartbeat. The filtered signal was then used to determine breathing frequency (f) and tidal volume (VT) by integration of the inspiratory (positive) part of the flow signal, and minute ventilation (VE) as f times VT. Time course data are shown as mean ± SEM averaged every 15 seconds. Separately, averages of 0-5 min, 5-15 min, and 15-25 min after the saline / drug treatment were compared to the baseline values (averaged over 15 minutes before the addition of fentanyl). In addition, as the nalfurafine response displayed a clear peak at 90 Seconds, values at 90 seconds across all conditions were also compared. These data are shown as mean ± SD. A one-way ANOVA with multiple comparisons and Fisher's Least Significant Difference (LSD) test was used to compare baseline values tothese time points within each condition. Individual time points were also compared between the saline group and each treatment. P<0.05 was considered significant.Example 1Effects of nalfurafine on high dose fentanyl induced rigidity

[0072] In a preclinical model (non-sedated rats) of opioid overdose that fentanyl acute intoxication both muscle rigidity and ventilation, clinical rigidity scores were determined as a result of dosing saline or nalfurafine (1 mg / kg) five minutes after one IV fentanyl doses (150 pg / kg). Nalfurafine restored suppressed the muscle rigidity (FIG. 1) caused by fentanyl. There were no additional effects on sedation or analgesia, which persisted following dosing of nalfurafine.Example 2Effects of nalfurafine and U50488 on the ventilatory depression produced by high dose fentanyl

[0073] The effect of saline, nalfurafine (0.1 and 1 mg / kg), and a pure kappa opioid receptor agonist, U50488 (1 and 10 mg / kg) on ventilation was tested by injection five minutes after a fentanyl injection (150 pg / kg over 15 seconds) in non-sedated adult rats. The five-minute postfentanyl period is indicated in each panel of FIG. 2 with a grey box. Note that during the phase of central apnea, the ventilatory signal was contaminated by a rhythmic expiratory activity and some gasps (bursts of inspiratory activity), which are not filtered in order to maintain the integrity of the data.

[0074] FIG. 4 shows representative data of the acute response to fentanyl followed by treatments. There was no difference in apnea onset or duration between individual treatment groups.

[0075] Baseline minute ventilation averaged 166.10 ± 68.24 ml / min, frequency 102.56 ± 17.67 b / min VT 1.38 ± 0.57 ml. An IV bolus injection of fentanyl (150 pg / kg, 15 seconds) produced an apnea in all rats with no exception occurring 17.69 ± 4.1 s into the injection. The timing was extremely consistent between animals as reflected by the low SD / mean ratio. The apnea lasted about 3 minutes (184 ± 74 sec).

[0076] Five minutes after fentanyl injection, all rats but one had already recovered a regular breathing pattern, while one rat still presented an apnea for 339 seconds. Overall minute ventilation averaged (85 ± 40 1 / min, ~ 50% of baseline ventilation) at the time of injections.

[0077] Five minutes after fentanyl injection, the injection of saline did not produce any change in breathing. Ventilation remained depressed by about 50% until the end of 30-minute period of study (FIG. 2). Ventilation continued to rise slowly to a plateau 7.5 min after fentanyl injection, but VE, frequency, and VT never returned to pre-fentanyl levels (FIGS. 2A, 2C, and 2E). Statistical comparisons of the averages of 5-10, 10-20, and 20-30-minute periods for each of VE, frequency, and VT are shown in FIG. 5. All three parameters remained significantly depressed compared to the pre-fentanyl baseline. The ratios of VE to oxygen consumption (V02) and carbon dioxide production (Vco2) are shown in FIG. 6. VE / VO2 was significantly depressed after injection of fentanyl, and VE / VCO2 was depressed in the 10-20 and the 20-30-minute periods.

[0078] Five minutes after fentanyl injection, animals received a 15-second bolus injection of nalfurafine at the dose 1 mg / kg (n=7) or 0.1 mg / kg (n=8), which was randomly selected. In contrast to the saline group, all the animals given 1 mg / kg nalfurafine showed a rapid and prolonged increase in breathing, reaching a peak in minute ventilation (237. 1 ± 71.74 ml / min, p<0.01) within 90 sec. The peak value was the only time point significantly above the pre- fentanyl levels, as breathing returned to near baseline for the remainder of the observation period. This was also true for the frequency (119 ± 39 versus 106 ± 9 b / min) and VT (1.7 ± 0.4 versus 1.2 ± 0.2 ml). This is in contrast to saline, where ventilation remained significantly below the baseline for the entirety of the 30 min. Ventilation subsided during the next 15 minutes towards the control levels but remained significantly higher than the saline group at 30 minutes (p,0.05). Delta changes in minute ventilation are shown in FIG. 2. Nalfurafine-treated rats had a higher VE (FIG. 5A) and VT (FIG. 5C) than saline, up to 30 minutes after treatment.

[0079] The lower, 0.1 mg / kg, nalfurafine dose was not able to significantly increase breathing. No peak was identifiable, yet VE (137 ± 35 ml / min) at the same timing as the 1 mg / kg peak response (90 seconds, see method section) was significantly higher than in the saline group (86 ± 28 ml / min). This stimulatory effect was not maintained over time, with both frequency and VT significantly depressed after 10 minutes. VE / VO2 and VE / VCO2 were not significantly different from baseline values, and VE / VCO2 was above the saline controls during the 10-20 and 20-30 minute periods (FIG. 6).

[0080] The group of rats that received 1 mg / kg U50488 (n=8) did not increase their breathing, unlike with 1 mg / kg nalfurafine. The response to U50488 was indistinguishable fromthe saline group. VE at 90 seconds and 5-10 min average were not different from baseline above the saline group at the same times (FIG. 5 A). However, this was not sustained, as the 10-20 min and 20-30 min average responses were significantly depressed compared to the baseline for the group. VE / VO2and VE / VCO2 were not different from baseline or saline levels for this dose (FIG. 6). Increasing the dose to 10 mg / kg had no stimulatory effect and was even lethal in 3 of the 4 rats studied.

[0081] In conclusion, any antidotal effect of a pure kappa agonist (U50488) on the severe breathing depression produced by a high dose bolus fentanyl injection was unable to be demonstrated, in major contrast to nalfurafine at the dose of 1 mg / kg.Example 3Effects of saline, nalfurafine, and U50488 on muscle rigidity and sedation produced by fentanyl

[0082] The effects of fentanyl on muscle rigidity and sedation. Before injection, the nonsedated animals were alert and responsive, with normal reflex activity. A bolus injection of fentanyl induced an immediate coma along with an abrupt tonic muscle rigidity which developed within 1 minute in all 18 rats. There were no differences among the three pre-treatment groups (FIGS. 3A and 3B). The contractions caused forelimb adduction, hindlimb flexion, sustained abdominal and back muscle contraction, and tail extension. Sedation indicators, including grasping, righting reflex, corneal reflex, and response to a clap, were suppressed immediately after fentanyl injection (FIGS. 3C and 3D). Forelimb toe pinch confirmed the lack of response to painful stimuli (FIGS. 3E and 3F). Reflex suppression remained consistent across all groups before treatment.

[0083] The effects of saline, nalfurafine, and U50488 on fentanyl-induced muscle rigidity (FIMR) and sedation. Administration of 1 mg / kg nalfurafine (n = 6) effectively reversed fentanyl-induced muscle rigidity within minutes, an effect sustained throughout the 30-minute observation period (FIG. 3A). In contrast, saline (2 ml / kg, n = 6) had no immediate effect, and U50488 (1 mg / kg, n = 6) produced only a transient reversal of rigidity. Five minutes after nalfurafine injection, rigidity scores (mean ± SD) were 0.7 ± 0.5 (arbitrary units) compared to 1.8 ± 0.4 for saline and 1.0 ± 0.4 for U50488. As shown in FIG. 3B, nalfurafine was significantly more effective at reversing FIMR than U50488. Reflex or painful stimuli responses to saline, nalfurafine, and U50488 were virtually identical over 30 minutes (FIGS. 3C and 3E). There wereno statistical differences between the groups when comparing the entire treatment period (FIGS. 3F and 3F). Of note, two animals in each of the saline and nalfurafine groups and one animal in the U50488 group woke up before the end of the 30-minute observation period. Those were scored as the absence of rigidity (0) and full reflex responses (2) for each group.Example 4Effect of Nalfurafine and U50488 alone

[0084] Nalfurafine (1 mg / kg) and the maximum tolerated dose of U50488 (1 mg / kg) were given to unsedated rats that were not exposed to fentanyl. Representative results are seen in FIGS. 7A and 7B. When administered alone, neither nalfurafine nor U50488 had any significant effect on breathing when compared to baseline (FIG. 7D). These drugs alone, in particular, nalfurafine (Img / kg), did not display any ventilatory stimulation or inhibition.

[0085] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.

[0086] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

[0087] Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIMS:

1. A method for treating opioid-induced respiratory depression and muscle rigidity in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of nalfurafine, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the subject received an overdose of an opioid.

3. The method of claim 1 or 2, wherein the subject received oral or topical exposure to or administration of the opioid.

4. The method of any of claims 1-3, wherein the subject received a dose of the opioid intravenously.

5. The method of claim 4, wherein the intravenous dose was administered at greater than 30 pg / min.

6. The method of any of claims 1-5, wherein the opioid is fentanyl or an analog thereof.

7. The method of any of claims 1-6, wherein the subject received a dose, overdose, or exposure to one or more opioids.

8. The method of claim 7, wherein the one or more opioids comprise fentanyl or an analog thereof.

9. The method of any of claims 1-8, wherein the muscle rigidity is chest wall muscle rigidity.

10. The method of any of claims 1-9, wherein the therapeutically effective dose of nalfurafine is administered intravenously, intramuscularly, subcutaneously, or intranasally.

11. The method of any of claims 1-10, wherein the therapeutically effective dose of nalfurafine is 0.01 mg / kg to 0.1 mg / kg administered intravenously.

12. The method of any of claims 1-11, wherein the method does not decrease sedation or analgesia level of the subject.

13. A kit comprising one or more therapeutically effective doses of nalfurafine and a delivery device or system.

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